By merging insights from numerous extensive datasets, MIT scholars have uncovered various new possible targets for addressing or averting Alzheimer’s disease.

The investigation uncovered genes and cellular pathways that had not previously been associated with Alzheimer’s, including one related to DNA repair. Discovering new drug targets is vital since many Alzheimer’s medications developed thus far have not yielded the anticipated success.

Collaborating with scientists from Harvard Medical School, the team utilized data from both humans and fruit flies to pinpoint cellular pathways connected to neurodegeneration. This enabled them to identify further pathways that may play a role in the onset of Alzheimer’s.

“All the evidence we possess suggests that there are numerous pathways involved in the advancement of Alzheimer’s. It is multifactorial, which may explain the challenges in creating effective medications,” states Ernest Fraenkel, the Grover M. Hermann Professor in Health Sciences and Technology in MIT’s Department of Biological Engineering and the lead author of the research. “We will require some sort of combination of treatments that target different aspects of this disease.”

Matthew Leventhal PhD ’25 serves as the principal author of the article, which is published today in Nature Communications.

Alternative pathways

Throughout recent decades, numerous studies have indicated that Alzheimer’s disease is caused by the accumulation of amyloid plaques in the brain, triggering a series of events that leads to neurodegeneration.

A limited number of medications have been created to obstruct or dismantle these plaques, but they typically do not have a significant impact on the progression of the disease. In an effort to find new drug targets, many scientists are now focusing on revealing other mechanisms that might contribute to Alzheimer’s development.

“One possibility is that perhaps there are multiple causes of Alzheimer’s, and that even within a single individual, various contributing factors may exist,” Fraenkel remarks. “So, even if the amyloid hypothesis holds — and some individuals disagree — it’s essential to identify those additional factors. Then, if we can address all the causes of the disease, we stand a better chance of preventing and potentially reversing some damages.”

To seek out these additional factors, Fraenkel’s lab collaborated with Mel Feany, a pathology professor at Harvard Medical School and a geneticist specializing in fruit fly genetics.

Utilizing fruit flies as a model, Feany and her colleagues conducted a screening process in which they knocked out nearly every conserved gene expressed in fly neurons. They then assessed whether each of these gene knockdowns influenced the age at which the flies exhibited neurodegeneration. This enabled them to pinpoint approximately 200 genes that hasten neurodegeneration.

Some of these have already been associated with neurodegeneration, including genes related to the amyloid precursor protein and proteins known as presenillins, which are involved in the formation of amyloid proteins.

The researchers subsequently analyzed this data using network algorithms that Fraenkel’s lab has been developing over recent years. These algorithms can reveal connections between genes that might be engaged in the same cellular pathways and functions.

In this instance, the objective was to link the genes identified in the fruit fly screening with specific processes and cellular pathways that may contribute to neurodegeneration. To accomplish this, the researchers integrated the fruit fly data with several additional datasets, including genomic information from postmortem tissue of individuals with Alzheimer’s.

The initial phase of their analysis unveiled that many of the genes found in the fruit fly study also diminish as humans age, indicating that they may be implicated in human neurodegeneration.

Network analysis

In the subsequent stage of their research, the scholars included further data pertinent to Alzheimer’s disease, such as eQTL (expression quantitative trait locus) data — a measure of how different gene variants influence the expression levels of specific proteins.

Applying their network optimization algorithms to this data, the researchers identified pathways that connect genes to their prospective roles in the development of Alzheimer’s. The team focused on two of these pathways for their new study.

The first pathway, previously unassociated with Alzheimer’s disease, pertains to RNA modification. The network suggested that when one or both of the genes in this pathway — MEPCE and HNRNPA2B1 — are absent, neurons become more susceptible to the Tau tangles that form in the brains of Alzheimer’s patients. The researchers validated this effect by knocking down those genes in studies utilizing fruit flies and human neurons derived from induced pluripotent stem cells (IPSCs).

The second pathway highlighted in this study is involved in DNA damage repair. This network comprises two genes called NOTCH1 and CSNK2A1, which have been previously linked to Alzheimer’s, but not in relation to DNA repair. Both genes are most recognized for their roles in regulating cellular growth.

In this study, the researchers discovered that in the absence of these genes, DNA damage accumulates in cells through two separate DNA-damaging pathways. Accumulation of unrepaired DNA has previously been shown to lead to neurodegeneration.

With these targets now identified, the researchers aspire to collaborate with other laboratories to explore whether drugs targeting these genes could enhance neuron health. Fraenkel and other scientists are working on utilizing IPSCs from Alzheimer’s patients to generate neurons suitable for evaluating such drugs.

“The quest for Alzheimer’s medications will be significantly accelerated when robust experimental systems are established,” he states. “We are reaching a point where innovative systems are converging. One consists of improved experimental models based on IPSCs, and the other comprises computational models enabling us to integrate vast amounts of data. Once these two advance concurrently, which is imminent, we anticipate some breakthroughs.”

The research received funding from the National Institutes of Health.